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Polarization dictates iron handling by inflammatory and alternatively activated macrophages
Open accessAbstract
BACKGROUND: Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes. DESIGN AND METHODS: Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells. RESULTS: M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize--albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective. CONCLUSIONS: Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).
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“tumour-associated macrophages may promote iron release in the tumour microenvironments40,41.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [40]
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Cites
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“M2 cells play a pivotal role in sustaining angiogenesis, wound repair and tumor growth.(41,42) These functions are associated with their ability to provide nutrients, including iron, to the healing tissues.”
BackgroundAlternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · cited 1×
“They involve specific well-defined gene signatures, which allow polarized macrophages to exert their biological functions.(16,19) The limited ability of M1 macrophages to recycle iron is possibly involved in the ability of these cells to control bacterial pathogenicity.”
BackgroundMacrophage activation and polarization
Martinez, F. O. (2008) · Frontiers in Bioscience · doi:10.2741/2692 · Cited by 3,160
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745 · cited 1×
“M1 macrophages differentiate under the control of cytokines produced by Th1 cells, and in turn sustain establishment and maintenance of Th1 responses.(3,39) Here we observed that M1 cells maintained the ability to present antigens to memory T cells even after iron depletion: this feature possibly allows them to keep a…”
BackgroundMartínez, F. O., Gordon, S., Locati, M., & Mantovani, A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.10.7303 · Cited by 2,399 · cited 1×
“They involve specific well-defined gene signatures, which allow polarized macrophages to exert their biological functions.(16,19) The limited ability of M1 macrophages to recycle iron is possibly involved in the ability of these cells to control bacterial pathogenicity.”
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Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells
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“Gene-expression profiling and data analysis Gene expression profiling analysis was carried out as described with minor modifications.(9) Total cellular RNA was extracted from M1 and M2 polarized macrophages using the RNeasy midi kit, following the manufacturer’s recommendations.”
MethodSelf-citationHeme oxygenase 1 is required for mammalian iron reutilization
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Cited by
Sorted by citations
Macrophage plasticity and polarization in tissue repair and remodelling
Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A., & Locati, M. (2013) · The Journal of Pathology · doi:10.1002/path.4133 · Cited by 2,384
Iron and cancer: more ore to be mined
Torti, S. V., & Torti, F. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3495 · Cited by 1,621
Progress in tumor-associated macrophage (TAM)-targeted therapeutics
Ngambenjawong, C., Gustafson, H. H., & Pun, S. H. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.04.010 · Cited by 858
“Legumain and transferrin receptor are two other target receptors overexpressed on M2-TAMs compared to M1TAMs but that are also present on several cancer cell types [200][201][202].”
Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death
Kapralov, A. A., Yang, Q., Dar, H. H., Tyurina, Y. Y., Anthonymuthu, T. S., Kim, R., Croix, C. M. S., Mikulska‐Ruminska, K., Liu, B., Shrivastava, I. H., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-019-0462-8 · Cited by 667
Kroner, A., Greenhalgh, A. D., Zarruk, J. G., Passos dos Santos, R., Gaestel, M., & David, S. (2014) · Neuron · doi:10.1016/j.neuron.2014.07.027 · Cited by 655
“M2-polarized cells are thought to be specialized for iron recycling by expressing molecules involved in iron uptake and export (Corna et al., 2010).”
Influential
Metadata
- Authors
- Corna, G., Campana, L., Pignatti, E., Castiglioni, A., Tagliafico, E., Bosurgi, L., Campanella, A., Brunelli, S., Manfredi, A. A., Apostoli, P., Silvestri, L., Camaschella, C., & Rovere-Querini, P.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- University of Modena and Reggio Emilia (IT)
- IRCCS Ospedale San Raffaele (IT)
- University of Brescia (IT)
- ORCID
- Venue
- Haematologica
- Published
- 2010-05-29
- Volume
- 95
- Issue
- 11
- Pages
- 1814-1822
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC2966902
- OpenAlex
- W2096008021
- Cited by
- 304
- References
- 47
- Citations by year
- 2026: 21 · 2025: 12 · 2024: 25 · 2023: 17 · 2022: 32 · 2021: 23 · 2020: 13 · 2019: 20 · 2018: 22 · 2017: 23 · 2016: 18 · 2015: 14 · 2014: 17 · 2013: 22 · 2012: 15
- FWCI
- 9.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Fondazione Cariplo
- Ministero della Salute
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- macrophage polarization, iron homeostasis, M1 macrophages, M2 macrophages, iron recycling, H-ferritin, transferrin receptor 1, ferroportin, iron regulatory proteins, labile iron pool, interferon-gamma, IL-4, T cell activation
- MeSH terms
- Ferroportin, Animals, Apoferritins, Gene Expression Regulation, Inflammation, Interferon-gamma, Iron, Lymphocyte Activation, Macrophage Activation, Macrophages, Receptors, Transferrin, T-Lymphocytes, Interleukin-4, Cation Transport Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Mice
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